Cathepsin E (Cath E) and Cathepsin D (Cath D), members of the aspartic proteolytic enzymes family, have very similar substrate selectivity. Unlike the relatively ubiquitous Cath D, Cath E has a limited cellular localization and tissue distribution. Cath E is contained mainly within vesicular structures associated with the endoplasmic reticulum and endosomal compartments of macrophages, gastric epithelial cells, lymphocytes, microglia, and dendritic cells. In contrast to Cath E, Cath D is known to be involved in various diseases, e.g., cancer growth, metastasis, Alzheimer's Disease, and several other diseases. Although Cath E and Cath D have different tissue localization, cellular distribution, and physiological function, they share many enzymatic characteristics including molecular weight (43 kDa), catalytic mechanism, substrate preferences, proteolytic conditions, and inhibition susceptibility. Both of them are aspartic endopeptidases, which prefer hydrophobic amino acid residues at P1 and P1′ positions of the scissile bond. Their optimal pH of proteolysis is between 3.5 and 5.0. A wide variety of peptidomimetic inhibitors are known for Cath E, but none can provide satisfactory discrimination against Cath D.
There are numerous methods of delivering therapeutics to subjects. These methods, however, are associated with multiple issues including toxicity, degradation of the therapeutic agent, and limited duration of efficacy of the therapeutic agent.